|E2A-HLF usurps control of evolutionarily conserved survival pathways|
|Markus G Seidel and A Thomas Look|
Pediatric Oncology Department, Dana-Farber Cancer Institute, 44 Binney Street, M-630, Boston, Massachusetts, MA 02115, USA
Correspondence to: A Thomas Look, Pediatric Oncology Department, Dana-Farber Cancer Institute, 44 Binney Street, M-630, Boston, Massachusetts, MA 02115, USA. E-mail: firstname.lastname@example.org
E2A-HLF, the chimeric fusion protein resulting from the leukemogenic translocation t(17;19), appears to employ evolutionarily conserved signaling cascades for its transforming and antiapoptotic functions. These arise from both impairment of normal E2A function and activation of a survival pathway triggered through the HLF bZip DNA binding and dimerization domain. Recent reports identify wild-type E2A as a tumor suppressor in T lymphocytes. Moreover, E2A-HLF has been shown to activate SLUG, a mammalian homologue of the cell death specification protein CES-1 in Caenorhabditis elegans, which appears to regulate an evolutionarily conserved cell survival program. Recently, several key mouse models have been generated, enabling further elucidation of these pathways on a molecular genetic level in vivo. In this review, we discuss the characteristics of both components of the fusion protein with regard to their contribution to the regulation of cell fate and the oncogenic potential of E2A-HLF. Oncogene (2001) 20, 5718-5725.
apoptosis; acute leukemia; chromosomal translocation; circadian rhythm; hepatic leukemia factor; developmental cell fate
The E2A-HLF fusion protein gives rise to a distinct but fortunately rare form of high risk pro-B-cell acute lymphoblastic leukemia (ALL) in adolescents. The unique clinical features of this disease, which often proves refractory to intensive chemotherapy and is frequently associated with disseminated intravascular coagulation and hypercalcemia at diagnosis, together with the apoptosis-linked oncogenic mechanisms of the fusion protein, have attracted considerable scientific attention (for previous reviews see Hunger, 1996; Look, 1997a,b; Ferrando and Look, 2000).
In addition to the translocation t(17;19)(q22;p13), which generates E2A-HLF, two other E2A translocations are involved in leukemias arising from early B-lineage progenitors. Most prevalent in childhood B lineage ALL is the t(1;19)(q23;p13), resulting in a fusion of E2A amino-terminal sequences, similar to those represented in E2A-HLF, to PBX1, the mammalian homologue of the major homeotic protein heterometric partner, extradenticle (Kamps et al., 1990; Nourse et al., 1990; Izraeli et al., 1992; Numata et al., 1993); for a review of E2A-PBX1, see C Murre, in this issue of Oncogene Reviews). A third, only recently described E2A chimeric gene, results from cryptic rearrangements of chromosome 19, apparently fusing 5 aminoterminal sequences of E2A with various fragments of a previously unknown gene located at the long arm of chromosome 19 (q13.4), called FB1 (Brambillasca et al., 1999). This region has been implicated in frequent cancer-associated loss of heterozygosity and is also thought to harbor tumor suppressor functions (Takeuchi et al., 1995; Maintz et al., 1997; Bicher et al., 1997; McDonald et al., 1998; Mehenni et al., 1997). The resultant E2A-FB1 fusion, like E2A-PBX1, gives rise to pre-B-ALL in children; however, the oncogenic mechanisms and prevalence of this newly identified E2A-fusion gene remain to be elucidated.
The E2A-HLF fusion protein contains the N-terminal transactivation domains of E2A joined to the basic region and leucine zipper domain of hepatic leukemia factor (HLF) (Inaba et al., 1992; Hunger et al., 1992). Two different types of genomic rearrangements leading to E2A-HLF fusion have been described (for reviews, see Look, 1997a; Hunger, 1996); both result in a functional protein that retains the DNA-binding capacity and transcriptional activation domains (Hunger et al., 1994). While E2A plays a major role in B-cell development and is usually expressed in lymphocytes, the expression of HLF is aberrantly driven by the E2A promoter when the fusion gene is expressed in pro-B lymphoblasts. Therefore, interference with normal E2A function as well as inappropriate HLF expression, and thereby altered transcriptional activity from the fusion transcription factor, are both likely to be important leukemogenic mechanisms employed by E2A-HLF. Finally, homozygous p16INK4A and p15INK4B deletions were reported in two E2A-HLF-positive cell lines, and hypermethylation of the p15 promoter was seen in one of two primary (t(17;19)+ leukemia specimens, providing clues to the other genetic alterations that may contribute to E2A-HLF-mediated leukemogenesis (Maloney et al., 1998).
E2A as a tumor suppressor
The family of basic region/helix-loop-helix (bHLH) transcription factors is characterized by a typical protein-nucleic acid interaction motif allowing for homo- or heterodimerization and sequence-specific DNA binding, and contains a variety of members that are implicated in lymphocytic development as well as leukemogenesis (E2A, Tal1/Sc1, Tal2, Lyl1, BHLHB1 (Murre et al., 1989a,b; Begley and Green, 1999; Baer, 1993; Wang et al., 2000). The E2A locus encodes three proteins, E12, E47 and E2-5, that are generated by alternative splicing and bind to specific E-box elements that are relevant in immunoglobulin and T-cell receptor gene rearrangements during development (Murre et al., 1989a,b; Sun and Baltimore, 1991; Henthorn et al., 1990a,b). Studies in genetically modified mice have increased the knowledge about E2A substantially. Two different knockout strategies yielded E2A null mice (Table 1; Bain et al., 1994; Zhuang et al., 1994) with a phenotype that included impaired immunoglobulin DJ and V(D)J gene rearrangements, but normal T-cell receptor gene rearrangements and normal myeloid cell development. These findings demonstrated the necessity of E2A proteins in B-cell formulation. The E2A-/- mouse models, as well as a third strategy based on overexpression of a bHLH-sequestering antagonist (the Id1 gene) in a transgenic approach (Table 1; Sun, 1994), showed B-cell maturation arrest at the earliest stage of committed B-lineage development, right after the cells have become common lymphoid progenitors. In addition, it has been shown that E2A is specifically induced during B-cell activation, and although not required for normal proliferation of mature B-cells, E2A is essential for immunoglobulin isotype class switching during B-cell activation (Quong et al., 1999).
T cell maturation and cell fate
B-cells are unique in that homodimers of E2A proteins (also referred to as class A bHLH proteins) are required for the proper E2A function (Bain et al., 1993; Murre et al., 1991; Shen and Kadesch, 1995), whereas in other parts of the body, tissue-specific bHLH proteins (class B, such as MyoD (muscle), Tal1 and Lyl1 (T cells), and NeuroD (neurons)) heterodimerize with E2A to cooperatively mediate bHLH functions. E2A is also highly expressed in thymocytes (Roberts et al., 1993; Sawada and Littman, 1993; Takeda et al., 1990), and T-cell-specific genes (eg. the TCR enhancer, CD4 enhancer and CD4 silencer) have been shown to contain E-box sites (Duncan et al., 1996; Sawada and Littman, 1993; Takeda et al., 1990), suggesting that E2A might also be important in T cells. A more recent finding, that a deficiency of E2A in E2A null mice or E2A antagonism in Id1-transgenic mice also leads to partial T-cell maturation arrest and the development of T-cell lymphomas, has led to the hypothesis that the T-cell leukemia oncoproteins Tal1 and Lyl1 act as dominant inhibitors of E2A (Table 1; Bain et al., 1997; Yan et al., 1997; Kim et al., 1999; Begley and Green, 1999). In particular, the downregulation of E47 activity has been shown to be critical for maturation and enhanced cell death of immature T-cells, and for positive selection of thymocytes (Bain et al., 1999). This study points out the similarity of the T-lineage phenotypes of E47-/- and Bcl-2 transgenic mice (such as alteration of the CD4/CD8 ratio), and emphasizes a possible role of cell fate regulation by E2A proteins.
In fact, other work from C Murre's laboratory (Engel and Murre, 1999) as well as a report from the laboratory of XH Sun (Park et al., 1999) confirmed, that apoptosis can be promoted by either ectopic expression of E47 or E12 in E2A-deficient lymphomas or by restoration of E47 activity in Jurkat cells, a Tal1-expressing T-cell line. These findings support the idea that the regulation of cell fate decisions, or facilitation of pro-apoptotic events, may be one of the functions of E2A. Thus, loss of normal E2A function may lead to aberrant survival, as suggested by the anti-apoptotic activity of amino-terminal fragments of E2A-HLF (Inukai et al., 1998). Thus, one mechanism of oncogenicity used by E2A-HLF might be impairment of normal E2A function. It is intriguing, that mice, engineered to constitutively overexpress E2A-HLF, develop T-cell lymphomas and B- and T-lineage maturation defects similar to those seen in E2A null or Id1 transgenic mice (Table 1; Honda et al., 1999; Smith et al., 1999; Kim et al., 1999). Collectively, these findings demonstrate a role of the E2A component of the fusion protein in the regulation of cell fate, suggesting that compromised E2A function may contribute to early B lineage leukemias in progenitors harboring the t(17;19).
Functions in cell cycle control
In addition to the function of E2A in cell fate decisions, bHLH proteins such as E2A and MyoD are involved in the induction of G1 cell cycle arrest (Peverali et al., 1994; Sorrentino et al., 1990). Correspondingly, the bHLH-sequestering Id proteins have been shown to promote G1-S transition (Barone et al., 1994; Hara et al., 1994). One molecule acting at that transition during cell cycle, p21CIP1/WAF1, an inhibitor of cyclin-dependent kinases (Cdk), was recently shown to be regulated by E2A and Id proteins (Prabhu et al., 1997). Other laboratories have demonstrated that Cdk-2-dependent phosphorylation of Id2 and Id3 prevents these proteins from antagonizing E2A-mediated cell cycle arrest (Hara et al., 1997; Deed et al., 1997). In addition, Chu and Kohtz (2001) have recently identified G1 Cdk sites in the amino-terminal domain of E12/E47 suggesting that E2A itself is a target of Cdk phosphorylation - mediated regulation. These studies implicate E2A as an integrating molecule in signals regulating G1-S phase cell cycle checkpoints.
In summary, E2A serves as a tumor suppressor par excellence, mediating essential functions in the regulation of differentiation, maturation, cell fate, and the cell cycle, so that modifications of its expression level likely contribute in important ways to leukemogenesis.
Both components of E2A-HLF contribute to leukemogenic pathways
Hepatic leukemia factor (HLF) and related genes
The DNA-binding specificity of E2A-HLF is distinct from that of E2A, due to in-frame fusion to the basic region/leucine zipper domains of hepatic leukemia factor. Thus it is likely that the transforming properties of E2A-HLF do not depend on perturbation of normal E2A function, but also on the induction of novel, potentially cancer-linked target genes of the chimeric fusion protein (Figure 1). In the fusion protein, the dimerization and DNA-binding domains of E2A are replaced by the corresponding domains of HLF. Together with DBP (albumin promoter D-box binding protein; Mueller et al., 1990), and TEF (thyrotroph embryonic factor; (Drolet et al., 1991), HLF belongs to the PAR (proline and acidic amino acid-rich) subfamily of bZIP transcription factors (Hunger et al., 1992; Inaba et al., 1992). By primary amino acid sequence similarity, it is closely related to the Drosophila gene vrille, a developmental transcription factor that plays a major role in circadian rhythm control. Vrille is regulated by the bHLH transcription factors (dCLOCK and CYCLE in an oscillating manner via E-box motifs and apparently acts by negatively regulating other clock genes, such as period and timeless (Blau and Young, 1999). Likewise, murine DBP mRNA was shown to oscillate not only in the liver and in other organs, but also in the suprachiasmatic nuclei of the hypothalamus, a region thought to comprise the central mammalian pacemaker (Wuarin et al., 1992; Fonjallaz et al., 1996; Lavery et al., 1996; Lopez-Molina et al., 1997). Recent publications suggest that DBP functions in part similarly to VRILLE in the mammalian clock, by virtue of its ability to regulate mPer1 and to be rhythmically induced by CLOCK (Yamaguchi et al., 2000; Ripperger et al., 2000). Although cycling expression levels of HLF and TEF have also been observed in various organs (Falvey et al., 1995; Fonjallaz et al., 1996), HLF did not appear to be highly expressed in the suprachiasmatic nuclei (Hitzler et al., 1999). Thus it is likely that other members of this protein family, more similar by amino acid sequence to the Drosophila protein VRILLE than HLF, e.g. DBP or NFIL3, may represent better candidates for VRILLE homologues in the mammalian circadian rhythm regulation pathways.
Recently, an in vitro study suggested a role of HLF alone or in combination with DBP in promoting the expression of Factor VIII and Factor IX genes in the liver, a function that could also be demonstrated for E2A-HLF (Begbie et al., 1999). It remains to be seen whether this finding is related to the clinical predisposition of t(17;19)+ ALL patients to present with disseminated intravascular coagulation.
Cell fate regulation by HLF-related genes
HLF expression in the brain and other organs during mouse development was studied extensively, because another closely related bZIP transcription factor with the same DNA-binding consensus site has been discovered to play a role in neuronal apoptosis, namely the Caenorhabditis elegans cell death specification protein CES-2, which is required for the regulated cell death of two sister cells of serotoninergic neurosecretory motor neurons during the development of the worm (Ellis and Horvitz, 1991; Metzstein et al., 1996). The CES-2 homologue E2A-HLF was shown to mediate survival of leukemia cells and to inhibit apoptosis after growth factor withdrawal from cell lines (Inaba et al., 1996), suggesting involvement of HLF in neuronal apoptosis. However, Hitzler et al. (1999) could not identify a role for HLF in developmentally regulated neuronal cell death.
NFIL3/E4BP4, encoded by an IL-3-regulated delayed early gene, is another HLF-related but PAR-deficient bZIP transcription factor that has been implicated in IL-3-mediated survival of pro-B lymphocytes (Cowell et al., 1992; Cowell and Hurst, 1994; Zhang et al., 1995; Ikushima et al., 1997; Kuribara et al., 1999). This putative role becomes very important with regard to the oncogenic transcription factor E2A-HLF, because the latter carries the same capacity to promote survival of murine hematopoietic cells if overexpressed in vitro. Thus, survival of native t(17;19)-harboring cells could be ascribed to constitutive activation of a survival pathway physiologically activated by hematopoietic growth factors via NFIL3 (Inaba et al., 1996; Ikushima et al., 1997; Kuribara et al., 1999). These results support the contention that E2A-HLF, through the aberrant localization of two trans-activating domains of E2A at pathological HLF-specific consensus sites, might actively employ a survival signaling pathway to perform its oncogenic functions. These effects apparently occur as a main oncogenic event in addition to the perturbation of normal E2A function in this leukemia (Figure 1). In fact, the CES-1-related zinc finger transcription factor SLUG is an upregulated target of E2A-HLF and promotes survival of hematopoietic cells if overexpressed in vitro in an analogous fashion to E2A-HLF (Inukai et al., 1999).
Functional domains of E2A-HLF
The ability of E2A-HLF to cause malignant transformation was demonstrated by induction of anchorage-independent growth of NIH3T3 fibroblasts in soft agar and subsequent tumor formation when these cells were transplanted in nude mice (Yoshihara et al., 1995). This oncogenic activity has been shown to require at least one of the two trans-activation domains of E2A, as well as the leucine zipper dimerization domain of HLF (Yoshihara et al., 1995). In addition, the transforming ability also depends on homodimerization of E2A-HLF (Inukai et al., 1997). However, the antiapoptotic function of E2A-HLF in vitro requires neither the basic (DNA-binding) region nor the leucine zipper domain needed for protein-protein dimerization (Inukai et al., 1998). Furthermore, in contrast to all other cell lines tested, the HAL-01 patient-derived t(17;19)-positive leukemia cell line, which harbors a point mutation within the leucine zipper region of HLF, does not express the E2A-HLF target gene SLUG on a level detectable by RT-PCR (Inukai et al., 1999). Consistent with these findings, deletion of the entire homeodomain of PBX1 did not impair the potential of the E2A-PBX1 fusion protein to transform fibroblasts as well as to induce thymoma in mice (Kamps et al., 1996; Monica et al., 1994). Moreover, the entire PBX1-derived portion of E2A-PBX1, which is comparable to the carboxy-terminal HLF part in E2A-HLF, can be replaced by DNA-binding/dimerization or even only dimerization motifs from other proteins, without losing the in vitro transforming potential of the intact oncoprotein. This hallmark of oncogenicity was completely retained even in the absence of PBX1 and depended only on dimerization of the E2A fragment of E2A-PBX1 (Bayly and LeBrun, 2000). Therefore, in both of the fusion proteins, E2A-HLF and E2A-PBX1, the E2A component appears to be sufficient to trigger oncogenic transformation if misexpressed and dimerized due to the fusion partner.
The striking hematopoietic similarity between two independently derived E2A-HLF transgenic mouse models, E2A-PBX1 transgenic mice, and E2A-deficient mice-in particular with regard to the emergence of increasingly immature lymphoid cell populations, lymphocytic maturation arrest and development of T cell lymphomas-lends further support to the conclusion that impairment of normal E2A function provides a central mechanism of oncogenesis (Table 1) (Smith et al., 1999; Honda et al., 1999; Dedera et al., 1993; Bain et al., 1994; Zhuang et al., 1994). However, Slug-deficient mice also show a phenotype of perturbed hematopoiesis and appear to be sensitive to DNA damage induced apoptosis within the hematopoietic compartment (Table 1; Inoue et al., 1999; Inoue et al., manuscript submitted). These findings indicate the operation of an exclusively E2A-HLF-mediated mechanism to promote the survival of lymphoblasts, one that is unconnected to impaired E2A function.
In summary, two characteristic features of E2A-HLF, loss of one E2A allele and abnormal expression of the HLF DNA-binding domain, likely contribute both efficiently and synergistically to the oncogenic properties of E2A-HLF.
SLUG and cell fate regulation by E2A-HLF
Slug and snail transcription factors in cancer
Slug belongs to the Slug/Snail family of evolutionarily conserved zinc finger transcriptional repressors (Boulay et al., 1987; Hemavathy et al., 2000b). Besides many functions in embryonic development, Snail-related proteins are also involved in carcinogenesis through aberrant regulation of apoptosis (Metzstein and Horvitz, 1999; Inukai et al., 1999; Grimes et al., 1996) and possibly an invasiveness/metastasis by regulating the expression of E-cadherins (Figure 1; Oda et al., 1998; Batlle et al., 2000; Cano et al., 2000; for review, see Hemavathy et al., 2000a). GFI-1, a more distant relative of SLUG in the SLUG/Snail family, is an oncoprotein that can render IL-2-dependent T cells growth factor independent and was shown to cause T cell lymphomas in transgenic mice (Gilks et al., 1993; Grimes et al., 1996). GFI-1 shares the SNAG (Snail and Gfi-1) transcriptional repressor domain with SLUG, and was shown to inhibit BAX in vitro and in primary cells of GFI-1-induced thymomas, supporting the hypothesis that SLUG/Snail family proteins, like CES-1, can regulate cell fate (Figure 1; Grimes et al., 1996). However, GFI-1 appears to be a rather weak oncogenic and requires cooperation with c-myc and pim in oncogenicity (Schmidt et al., 1998). PAG-3, a GFI-1 homologue in C. elegans, is a zinc-finger transcription factor involved in neuronal development and is thought to share functional properties with GFI-1 (Jia et al., 1997). A clear prediction is that PAG-3 may also play a role in cell fat decisions during C. elegans development.
Target genes of E2A-HLF and an evolutionarily conserved apoptosis program
Inukai et al. (1999) identified human SLUG as a target gene of E2A-HLF by representational difference analysis of RNA pools obtained from a t(17;19)+ leukemia patient cell line, which was stably transfected with an inducible dominant negative form of E2A-HLF (Inukai et al., 1999). Other genes identified in this screen as being upregulated in an E2A-HLF-dependent manner also serve as potential downstream targets of E2A-HLF, namely, ANNEXIN VIII and SRPUL (sushi repeat protein upregulated in leukemia) (Kurosawa et al., 1999). However, the latter two genes could not prevent apoptosis when overexpressed in murine IL-3-dependent leukemia cell lines, suggesting that they are not causally involved in the antiapoptotic functions of E2A-HLF (Kurosawa et al., 1999). As pointed out previously, the E2A-HLF oncogene is closely related to ces-2, a cell death specification gene in Caenorhabditis elegans (Metzstein et al., 1996; Inaba et al., 1996). By amino acid sequence homology and functional properties as a target of E2A-HLF, SLUG represents a mammalian homologue of CES-1, which acts downstream of CES-2 in C. elegans (Figure 1; Metzstein and Horvitz, 1999; Inukai et al., 1999). Ces-2 and ces-1 control programmed cell death in sister cells of neurosecretory motor neurons during development in C. elegans (Ellis and Horvitz, 1991; Metzstein et al., 1996, 1998; Metzstein and Horvitz, 1999). The resemblance of cell death pathways including CES-2/CES-1 in the worm and E2A-HLF/SLUG in human pro-B leukemia suggested that SLUG might have an important regulatory role in the survival of lymphoid or other types of hematopoietic cells. In the worm, downregulation of ces-1 to abolish the CES-1-mediated repression of EGL-1 promotes the developmental cell death of two neuronal sister cells of neurosecretory motor neurons. EGL-1, the C. elegans homologue of pro-apoptotic Bcl-2 family members, contains a BH3 (Bcl-2 homology) domain and is required to sequester CED-9 from CED-4 leading to activation of CED-3, which are the homologues of the Bcl-2, Apaf-1 and caspase-9 mammalian mediators of the apoptosis cascade (Metzstein and Horvitz, 1999). According to this model, SLUG may inhibit mitochondrial dysfunction and the cytochrome c/Apaf-1/caspase-9 apoptotic pathway by transcriptionally downregulating one of the mammalian EGL-1 homologs, e.g., BID/BAX/BAK, whose interaction plays a major role in caspase-9 activation (Figure 2; Inukai et al., 1999; Lindsten et al., 2000).
Jiang et al. (1998) reported that mice lacking Slug are fertile but show postnatal growth delay and eyelid abnormalities; their mesoderm and neural crest development appeared normal. Inoue et al. (1999) independently derived a Slug-deficient mouse model to investigate the role of Slug in hematopoiesis and apoptosis. As summarized in Table 1, Inoue and colleagues observed increased numbers of clonogenic hematopoietic progenitors in the bone marrow and spleen of Slug-/- knockout mice, although the peripheral blood cell counts were normal, possibly reflecting a feedback loop to compensate for loss of differentiating hematopoietic cells (Inoue et al., 1999; Inoue et al., manuscript submitted). Slug-deficient mice also showed enhanced hematopoietic cell destruction when challenged with total-body -irradiation, given as a DNA-damaging agent. This effect could be prevented by a single-dose treatment with a truncated pegylated form of megakaryocyte growth and development factor (MGDF), which acts as a survival factor for myeloid cells. These results suggest that hematopoietic cells in these mice might be prone to apoptosis (Inoue et al., manuscript submitted). The study by Inoue et al. implicates SLUG as a survival factor in normal hematopoietic cell development and supports the model of cooperative oncogenic signaling triggered by the two components of the E2A-HLF fusion protein.
Future research will focus on the identification of downstream targets of the E2A-HLF/SLUG pathway in promoting the aberrant survival of lymphoid leukemia cells. The death specification pathways normally regulated by Slug will also be important areas for study, given that Slug expression appears to be aberrantly activated by E2A-HLF and not normally expressed by early B cell progenitors. Genetically engineered animal models lacking components of evolutionarily conserved apoptosis signaling cascades represent a powerful tool for identifying these cell death specification pathways and defining their roles in normal hematopoiesis.
The authors thank John Gilbert for editorial review and Stephen P Hunger and David W Sternberg Jr for reading the manuscript and their critical comments.
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Figure 1 Cell fate pathways regulated by E2A, HLF and related bZip proteins, SLUG and related zinc finger transcription factors, and the E2A-HLF chimera
Figure 2 Models for the roles of CES-1 and SLUG in apoptosis. (Right) Programmed cell death of NSM sister neurons during C. elegans development involves downregulation of CES-1, which in turn directly or indirectly leads to increased activity of the BH3-only cell death protein, EGL-1. (Left) In pro-B leukemia cells, the CES-1 related protein, SLUG, is postulated to act through the downregulation of mammalian BH3-containing proteins to promote the aberrant survival of cells with defective immunoglobulin genes that ordinarily would be targeted for apoptotic cell death (see Inukai et al., 1998)
Table 1 Mouse models relevant to the roles of E2A and E2A-HLF
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